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Li X, Zhou W, Zhou L, Li Y, Wu X, Chen J. Neutrophil-derived exosomal S100A8 aggravates lung injury in sepsis by inducing pyroptosis. Mol Immunol 2025; 181:29-39. [PMID: 40056630 DOI: 10.1016/j.molimm.2025.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 02/11/2025] [Accepted: 03/01/2025] [Indexed: 03/10/2025]
Abstract
Acute lung injury (ALI) is a common and life-threatening complication in patients with sepsis, with pro-inflammatory cell pyroptosis playing a crucial role in the associated organ damage. In this study, we aimed to identify potential therapeutic targets. Utilizing the GEO database (GSE232753), we analyzed the differentially expressed genes in the peripheral blood of healthy individuals and sepsis patients, identifying the significantly upregulated gene S100A8. Subsequently, we constructed a septic ALI model using lipopolysaccharide (LPS). Notably, S100A8 was highly expressed not only in serum and bronchoalveolar lavage fluid (BALF) but also in neutrophil exosomes. We then co-incubated BEAS-2B cells with neutrophil exosomes that were either treated or untreated with LPS. Cell proliferation activity was assessed using the CCK-8 assay, cell death was evaluated through propidium iodide (PI) staining, and the changes in pyroptosis indicators were detected via Western blot and ELISA. To further validate that LPS-induced neutrophil exosomes promote BEAS-2B cell pyroptosis through the delivery of S100A8, we conducted additional experiments involving the addition of S100A8 protein alone or S100A8 antibody in conjunction with neutrophil exosome treatment, followed by relevant assessments. Moreover, in vivo validation was also performed. Mechanistically, we revealed that S100A8 induces pyroptosis in BEAS-2B cells through the TLR4 signaling pathway. In conclusion, our findings provide new promising targets for the treatment of septic ALI.
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Affiliation(s)
- Xinxin Li
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China
| | - Wei Zhou
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China
| | - Liangliang Zhou
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China
| | - Yingbin Li
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China
| | - Xufeng Wu
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China
| | - Jianjun Chen
- Department of Emergency Intensive Care Medicine & Emergency Medicine, The First People's Hospital of Yancheng, Yancheng First Hospital Affiliated Nanjing University Medical College, Yancheng, Jiangsu 224000, China.
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2
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Shi J, Chen L, Yuan X, Yang J, Xu Y, Shen L, Huang Y, Wang B, Yu F. A potential XGBoost Diagnostic Score for Staphylococcus aureus bloodstream infection. Front Immunol 2025; 16:1574003. [PMID: 40330459 PMCID: PMC12052945 DOI: 10.3389/fimmu.2025.1574003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 03/31/2025] [Indexed: 05/08/2025] Open
Abstract
Staphylococcus aureus (S. aureus) bloodstream infection is often life-threatening, and increasing in incidence. We identified 63 differentially expressed genes (DEGs) in the GSE33341 S. aureus infection samples. Subsequently, intersecting the 63 DEGs with 950 genes from the blue module through weighted gene co-expression network analysis (WGCNA) yielded 38 genes. We leveraged Boruta and least absolute shrinkage and selection operator (LASSO) algorithms and identified5 diagnostic genes (DRAM1, UPP1, IL18RAP, CLEC4A, and PGLYRP1). Comparative analysis revealed that Extreme Gradient Boosting (XGBoost) surpassed SVM-RFE and Random Forest models, demonstrating superior diagnostic performance for S. aureus bloodstream infection (mean AUC for XGBoost =0.954; mean AUC for SVM-RFE =0.93275; mean AUC for Random Forest =0.94625). The XGBoost Diagnostic Score correlated with multiple immune cells to varying degrees, manifesting significant negative associations with CD8 T cells and CD4 naive T cells in both human and mouse samples. The diagnostic power of the Diagnostic Score was further validated by RT-qPCR results obtained from both mouse and patient samples, as well as RNA-Seq analysis conducted on mouse samples. XGBoost Diagnostic Score, consisting of DRAM1, UPP1, IL18RAP, CLEC4A, and PGLYRP1, may serve as a Diagnostic tool for S. aureus bloodstream infection.
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Affiliation(s)
- Junhong Shi
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lan Chen
- Department of Clinical Laboratory Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Xinru Yuan
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jinjin Yang
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yanlei Xu
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li Shen
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yu Huang
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Bingjie Wang
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fangyou Yu
- Department of Clinical Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of Respiratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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Ma W, Tang S, Yao P, Zhou T, Niu Q, Liu P, Tang S, Chen Y, Gan L, Cao Y. Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies. Signal Transduct Target Ther 2025; 10:75. [PMID: 40050633 PMCID: PMC11885678 DOI: 10.1038/s41392-025-02127-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 12/27/2024] [Accepted: 12/27/2024] [Indexed: 03/09/2025] Open
Abstract
In recent years, the incidence of acute respiratory distress syndrome (ARDS) has been gradually increasing. Despite advances in supportive care, ARDS remains a significant cause of morbidity and mortality in critically ill patients. ARDS is characterized by acute hypoxaemic respiratory failure with diffuse pulmonary inflammation and bilateral edema due to excessive alveolocapillary permeability in patients with non-cardiogenic pulmonary diseases. Over the past seven decades, our understanding of the pathology and clinical characteristics of ARDS has evolved significantly, yet it remains an area of active research and discovery. ARDS is highly heterogeneous, including diverse pathological causes, clinical presentations, and treatment responses, presenting a significant challenge for clinicians and researchers. In this review, we comprehensively discuss the latest advancements in ARDS research, focusing on its heterogeneity, pathophysiological mechanisms, and emerging therapeutic approaches, such as cellular therapy, immunotherapy, and targeted therapy. Moreover, we also examine the pathological characteristics of COVID-19-related ARDS and discuss the corresponding therapeutic approaches. In the face of challenges posed by ARDS heterogeneity, recent advancements offer hope for improved patient outcomes. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.
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Affiliation(s)
- Wen Ma
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Songling Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Yao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tingyuan Zhou
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China
| | - Qingsheng Niu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Liu
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Shiyuan Tang
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Yao Chen
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Gan
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
| | - Yu Cao
- Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, China.
- Institute for Disaster Management and Reconstruction, Sichuan University-The Hong Kong Polytechnic University, Chengdu, China.
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Mai DN, Nguyen Thi MA, Nguyen TT, Vu HA, Nguyen PNT. Protective role of olfactomedin 4 gene polymorphisms in preterm neonates with sepsis. Early Hum Dev 2025; 202:106223. [PMID: 39987659 DOI: 10.1016/j.earlhumdev.2025.106223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/10/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND Olfactomedin 4 (OLFM4) gene polymorphisms have been associated with variations in inflammatory responses and the severity of infections. This study aimed to investigate the association between OLFM4 single nucleotide polymorphisms (SNPs) rs17552047 and rs1891944 and severe outcomes in preterm neonatal sepsis. METHODS A prospective observational cohort study was conducted from April 2023 to April 2024, involving all preterm infants diagnosed with neonatal sepsis. Genotyping was performed using real-time polymerase chain reaction, and the associations with severe outcomes were analyzed using genetic models (dominant, recessive, and additive) through multivariate logistic regression and survival analysis. RESULTS Among the 174 preterm newborns included in the study, 39 experienced severe outcomes. The AA/AG genotypes of SNP rs17552047 and TT/TC genotypes of rs1891944 were associated with a reduced risk of severe outcomes (adjusted hazard ratio: 0.271, 95 % confidence interval [CI]: 0.115-0.641, p = 0.003, and adjusted hazard ratio: 0.349, 95 % CI: 0.175-0.698, p = 0.003, respectively). The odds of severe outcomes decreased by 65 % for each additional A allele (95 % CI: 0.15-0.78, p = 0.01). The model incorporating both SNPs and clinical variables demonstrated good predictive capability (area under the receiver operating characteristic curve: 0.826, 95 % CI: 0.748-0.903, p = 0.03). CONCLUSIONS The OLFM4 rs17552047 AA/AG and rs1891944 TT/TC genotypes have been linked to favorable outcomes in neonatal sepsis. These SNPs hold promise for predicting severe outcomes in neonatal sepsis.
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Affiliation(s)
- Duong Ngoc Mai
- Department of Pediatrics, University of Health Sciences, Vietnam National University, Ho Chi Minh City, Viet Nam; Department of Neonatology 2 - Metabolism - Clinical Genetics, Children's Hospital 1, Ho Chi Minh City, Viet Nam.
| | - Mai Anh Nguyen Thi
- Department of Pediatrics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam; Dengue Hemorraghic Fever and Hematology Department, Children's Hospital 1, Ho Chi Minh City, Viet Nam.
| | - Thu-Tinh Nguyen
- Department of Pediatrics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam; Neonatal Intensive Care Unit, Children's Hospital 2, Ho Chi Minh City, Viet Nam; Department of Neonatology, University Medical Center, Ho Chi Minh City, Viet Nam.
| | - Hoang Anh Vu
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam.
| | - Phung Nguyen The Nguyen
- Department of Pediatrics, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Viet Nam; Infectious Diseases of Intensive Care Unit, Children's Hospital 1, Ho Chi Minh City, Viet Nam.
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Ye R, Wei Y, Li J, Zhong Y, Chen X, Li C. Plasma-derived extracellular vesicles prime alveolar macrophages for autophagy and ferroptosis in sepsis-induced acute lung injury. Mol Med 2025; 31:40. [PMID: 39901167 PMCID: PMC11792199 DOI: 10.1186/s10020-025-01111-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 01/30/2025] [Indexed: 02/05/2025] Open
Abstract
Sepsis-induced acute respiratory distress syndrome (ARDS) is a severe complication of sepsis and the leading cause of mortality. Although the role of alveolar macrophages (AMs) in stabilizing pulmonary homeostasis is well established, the effects of circulating extracellular vesicles (EVs) on AMs remain largely unknown. In this study, an investigation was conducted to map the miRNA and protein expression profiles of EVs derived from septic plasma. Notably, EV-based panels (miR-122-5p, miR-125b-5p, miR-223-3p, OLFM4, and LCN2) have been found to be associated with the severity or prognosis of sepsis, with promising AUC values. Moreover, the levels of LCN2, miR-122-5p, and miR-223-3p were identified as independent predictors of septic ARDS. The in vitro coculture results revealed that the effects of LPS-EVs from the plasma of sepsis-induced acute lung injury (ALI), which carry pro-inflammatory EVs, were partly mediated by miR-223-3p, as evidenced by the promotion of inflammation, autophagy and ferroptosis in AMs. Mechanistically, the upregulation of miR-223-3p in LPS-EVs triggers autophagy and ferroptosis in AMs by activating Hippo signaling via the targeting of MEF2C. In vivo, the inhibition of miR-223-3p effectively mitigated LPS-EV-induced inflammation and AM death in the lungs, as well as histological lesions. Overall, miR-223-3p in LPS-EVs contributes to sepsis-induced ALI by priming AMs for autophagy and ferroptosis through the MEF2C/Hippo signaling pathway. These findings suggest a novel mechanism of plasma-AM interaction in sepsis-induced ALI, offering a plausible strategy for assessing septic progression and treating lung injury.
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Affiliation(s)
- Rongzong Ye
- Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Yating Wei
- Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Jingwen Li
- Guangxi Medical University, Nanning, 530021, China
| | - Yu Zhong
- Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Xiukai Chen
- Department of Critical Care Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, 361000, China.
| | - Chaoqian Li
- Department of Emergency Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China.
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Gong F, Zheng X, Xu W, Xie R, Liu W, Pei L, Zhong M, Shi W, Qu H, Mao E, Yang Z, Li R, Chen E, Chen Y. H3K14la drives endothelial dysfunction in sepsis-induced ARDS by promoting SLC40A1/transferrin-mediated ferroptosis. MedComm (Beijing) 2025; 6:e70049. [PMID: 39822760 PMCID: PMC11733091 DOI: 10.1002/mco2.70049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 01/19/2025] Open
Abstract
Pulmonary endothelial cell (EC) activation is a key factor in acute respiratory distress syndrome (ARDS). In sepsis, increased glycolysis leads to lactate buildup, which induces lysine lactylation (Kla) on histones and other proteins. However, the role of protein lactylation in EC dysfunction during sepsis-induced ARDS remains unclear. Integrative lactylome and proteome analyses were performed to identify the global lactylome profile in the lung tissues of septic mice. Cut&Tag analysis was used to identify the transcriptional targets of histone H3 lysine 14 lactylation (H3K14la) in ECs. Septic mice presented elevated levels of lactate and H3K14la in lung tissues, particularly in pulmonary ECs. Suppressing glycolysis reduced both H3K14la and EC activation, suggesting a link between glycolysis and lactylation. Moreover, H3K14la was enriched at promoter regions of ferroptosis-related genes such as transferrin receptor (TFRC) and solute carrier family 40 member 1 (SLC40A1), which contributed to EC activation and lung injury under septic conditions. For the first time, we reported the role of lactate-dependent H3K14 lactylation in regulating EC ferroptosis to promote vascular dysfunction during sepsis-induced lung injury. Our findings suggest that manipulation of the glycolysis/H3K14la/ferroptosis axis may provide novel therapeutic approaches for sepsis-associated ARDS.
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Affiliation(s)
- Fangchen Gong
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Xiangtao Zheng
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Wen Xu
- Department of Critical Care MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Rongli Xie
- Department of General SurgeryRuijin Hospital Lu Wan BranchShanghai Jiaotong University School of MedicineShanghaiP.R. China
| | - Wenbin Liu
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Lei Pei
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Ming Zhong
- Department of Critical Care MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Wen Shi
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Hongping Qu
- Department of Critical Care MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Enqiang Mao
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Zhitao Yang
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Ranran Li
- Department of Critical Care MedicineRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
| | - Erzhen Chen
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
- Shanghai Institute of Aviation MedicineShanghai Jiao Tong University Medical School Affiliated Ruijin HospitalShanghaiP.R. China
| | - Ying Chen
- Department of EmergencyRuijin HospitalShanghai Jiao Tong University School of MedicineShanghaiP.R. China
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Xia Q, Liu G, Zhang L, Xie B, Deng L. Anemonin suppresses sepsis-induced acute lung injury by inactivation of nuclear factor-kappa B and activation of nuclear factor erythroid 2-related factor-2/heme oxygenase-1 pathway. FASEB J 2025; 39:e70328. [PMID: 39825692 DOI: 10.1096/fj.202401987rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/27/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025]
Abstract
Sepsis-induced acute lung injury (ALI) is a common acute and severe reason of death in the intensive care unit. Although the pathogenesis is complicated and multifactorial, elevated inflammation and oxidative stress are considered as fundamental mechanisms for the progression of ALI. Anemonin is a natural compound with diverse biological properties including anti-inflammatory and anti-oxidative effects. To identify whether anemonin has protective effects on sepsis-induced ALI, a mouse sepsis-induced ALI model and cellular models using the mouse alveolar macrophage MH-S cells and mouse lung epithelial MLE-12 cells were established. Our results showed that anemonin reduced lipopolysaccharide (LPS)-induced mortality, and improved sepsis-induced ALI in the mouse model, as shown by improved histopathological changes, decreased lung wet/dry weight ratio, and myeloperoxidase activity. Anemonin alleviated LPS-induced secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid samples, as well as reversed the LPS-caused increase in malondialdehyde (MDA) content and decrease in activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lung tissues. In the cellular model, anemonin inhibited the LPS-induced inflammatory responses and oxidative stress in MH-S and MLE-12 cells. In addition, anemonin inhibited LPS-induced nuclear factor-kappa B (NF-κB) pathway, while enhancing the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) in lung tissues, MH-S, and MLE-12 cells. NF-κB inhibition enhanced the anti-inflammatory and anti-oxidative effects of anemonin, while Nrf2 knockdown attenuated these effects of anemonin, implying the critical roles of NF-κB and Nrf2. These results indicated that anemonin suppressed sepsis-induced acute lung injury by inhibition of NF-κB and activation of Nrf2/heme oxygenase-1 pathway, suggesting that anemonin might be developed as a new therapeutic agent for the treatment of sepsis-induced ALI.
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Affiliation(s)
- Qingping Xia
- Department of Science and Education, Gaozhou People's Hospital, Maoming, China
| | - Guohao Liu
- Department of Medical Imaging, Affiliated Hospital of Jilin Medical University, Jilin, China
| | - Liangqing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Baodong Xie
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Li Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
- Department of Cardiovascular Surgery, Gaozhou People's Hospital, Maoming, China
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Ouyang J, Wang H, Gan Y, Huang J. Uric acid mediates kidney tubular inflammation through the LDHA/ROS/NLRP3 pathway. Clin Exp Hypertens 2024; 46:2424834. [PMID: 39488824 DOI: 10.1080/10641963.2024.2424834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 09/26/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024]
Abstract
PURPOSE Hyperuricemia (HUA) is an important factor leading to chronic kidney disease (CKD). The kidney tubular inflammatory response is activated in HUA. This study aimed to investigate whether lactate dehydrogenase A (LDHA) is involved in mediating uric acid-induced kidney tubular inflammatory response. METHODS In vivo, an HUA mouse model was established by continuous intraperitoneal injection of potassium oxonate (PO) for one week. A total of 18 C57BL/6J male adult mice were divided into three groups: control group, HUA group, and HUA+oxamate group, with six mice in each group. Oxamate was intraperitoneally injected into the mice one hour after PO injection. In vitro, an HUA model was simulated by stimulating HK-2 cells with uric acid. Oxamate and tempol inhibited LDHA and reactive oxygen species (ROS) in HK-2 cells. RESULTS In HUA mice, blood uric acid levels were significantly elevated. LDHA in kidney tubular cells was significantly increased in both in vivo and in vitro HUA models, accompanied by an increase in kidney tubular inflammation and ROS. Mechanistically, LDHA mediates uric acid-induced inflammation to kidney tubular cells through the ROS/NLRP3 pathway. Pharmacologic inhibition of LDHA or ROS in kidney tubular cells can significantly ameliorate inflammation response caused by uric acid. CONCLUSIONS LDHA in kidney tubular cells significantly was increased in HUA models. LDHA mediates kidney inflammation response induced by uric acid through the ROS/NLRP3 pathway. This study may provide a new intervention target for preventing kidney tubular inflammation caused by uric acid.
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Affiliation(s)
- Jun Ouyang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hui Wang
- School of Pharmacy, Guangxi Medical University, Nanning, China
| | - Yumei Gan
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiangnan Huang
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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9
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Liu Y, Guo L, Zhang G, Sun W, Yang X, Liu Y. Nogo-A exacerbates sepsis-associated encephalopathy by modulating microglial SHP-2/NLRP3 balance and inducing ROS and M1 polarization. BIOMOLECULES & BIOMEDICINE 2024; 25:210-225. [PMID: 39151100 PMCID: PMC11647263 DOI: 10.17305/bb.2024.10822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 08/18/2024]
Abstract
Sepsis, a systemic inflammatory response caused by infection, can lead to sepsis-associated encephalopathy (SAE), characterized by brain dysfunction without direct central nervous system infection. The pathogenesis of SAE involves blood-brain barrier disruption, neuroinflammation and neuronal death, with neuroinflammation being the core process. Nogo-A, a neurite growth-inhibitory protein in the central nervous system, is not well understood in sepsis. This study explores Nogo-A's mechanisms in sepsis, focusing on SAE. Using in vivo and in vitro methods, healthy SPF C57BL/6J male mice were divided into Sham, Nogo-A-NC-Model, and Nogo-A-KD-Model groups, with sepsis induced by abdominal ligation and puncture. Morris water maze tests assessed learning and memory, and brain tissues underwent hematoxylin-eosin (HE) staining, Nissl staining, and Western blot analysis. In vitro, Nogo-A gene knockdown models were constructed using BV-2 microglia cells to study inflammation and oxidative stress. Results showed Nogo-A expression affected learning and memory in septic mice, with knockdown reducing neuronal damage. Bioinformatics analysis suggested Nogo-A may activate reactive oxygen species (ROS) to inhibit p-SHP2, activating mitochondrial autophagy and promoting neuronal apoptosis. Western blot results confirmed that Nogo-A affects mitochondrial autophagy and neuronal survival by inhibiting SHP2 and activating ROS. Nogo-A's role in neuroinflammation and neuroprotection was emphasized, revealing its impact on endoplasmic reticulum (ER) stress, mitochondrial autophagy, and NLRP3 inflammasome activation. This study provides a theoretical basis for SAE treatment, suggesting further multi-gene and multi-pathway analyses and validation in clinical samples. Developing gene therapy and drug interventions targeting Nogo-A pathways will offer more effective treatment strategies.
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Affiliation(s)
- Ying Liu
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, China
| | - Lei Guo
- Department of Clinical Laboratory, Cangzhou Central Hospital, Cangzhou, China
| | - Guoan Zhang
- University Nanobody Application Technology Research and Development Center of Hebei Provice, Cangzhou, China
| | - Wenjie Sun
- Science and Technology Experiment Center, Cangzhou Medical College, Cangzhou, China
| | - Xiaohui Yang
- University Nanobody Application Technology Research and Development Center of Hebei Provice, Cangzhou, China
| | - Yingfu Liu
- University Nanobody Application Technology Research and Development Center of Hebei Provice, Cangzhou, China
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10
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Tsakiroglou M, Evans A, Doce-Carracedo A, Little M, Hornby R, Roberts P, Zhang E, Miyajima F, Pirmohamed M. Gene Expression Dysregulation in Whole Blood of Patients with Clostridioides difficile Infection. Int J Mol Sci 2024; 25:12653. [PMID: 39684365 DOI: 10.3390/ijms252312653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 11/19/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Clostridioides difficile (C. difficile) is a global threat and has significant implications for individuals and health care systems. Little is known about host molecular mechanisms and transcriptional changes in peripheral immune cells. This is the first gene expression study in whole blood from patients with C. difficile infection. We took blood and stool samples from patients with toxigenic C. difficile infection (CDI), non-toxigenic C. difficile infection (GDH), inflammatory bowel disease (IBD), diarrhea from other causes (DC), and healthy controls (HC). We performed transcriptome-wide RNA profiling on peripheral blood to identify diarrhea common and CDI unique gene sets. Diarrhea groups upregulated innate immune responses with neutrophils at the epicenter. The common signature associated with diarrhea was non-specific and shared by various other inflammatory conditions. CDI had a unique 45 gene set reflecting the downregulation of humoral and T cell memory functions. Dysregulation of immunometabolic genes was also abundant and linked to immune cell fate during differentiation. Whole transcriptome analysis of white cells in blood from patients with toxigenic C. difficile infection showed that there is an impairment of adaptive immunity and immunometabolism.
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Affiliation(s)
- Maria Tsakiroglou
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
| | - Anthony Evans
- Computational Biology Facility, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool L69 7BE, UK
| | - Alejandra Doce-Carracedo
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
- Clinical Directorate, GCP Laboratories, University of Liverpool, Liverpool L7 8TX, UK
| | - Margaret Little
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
| | - Rachel Hornby
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
| | - Paul Roberts
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
- Faculty of Science and Engineering, School of Biomedical Science and Physiology, University of Wolverhampton, Wolverhampton WV1 1LZ, UK
| | - Eunice Zhang
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
| | - Fabio Miyajima
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
- Oswaldo Cruz Foundation (Fiocruz), Branch Ceara, Eusebio 61773-270, Brazil
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, Institute of Systems Molecular and Integrative Biology, University of Liverpool, Liverpool L69 3GL, UK
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11
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Wu J, Cao X, Huang L, Quan Y. Construction of a NETosis-related gene signature for predicting the prognostic status of sepsis patients. Heliyon 2024; 10:e36831. [PMID: 39281624 PMCID: PMC11400959 DOI: 10.1016/j.heliyon.2024.e36831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 08/22/2024] [Accepted: 08/22/2024] [Indexed: 09/18/2024] Open
Abstract
Background Sepsis is a common traumatic complication of response disorder of the body to infection. Some studies have found that NETosis may be associated with the progression of sepsis. Methods Data of the sepsis samples were acquired from Gene Expression Omnibus (GEO) database. Gene set enrichment score was calculated using single-sample gene set enrichment analysis (ssGSEA). Weighted gene co-expression network analysis (WGCNA), protein-protein interaction (PPI) networks analysis, and stepwise multivariable regression analysis were performed to identify NETosis-associated genes for sepsis prognosis. To assess the infiltration of immune cells, the ESTIMATE and CIBERPSORT algorithms were used. Functional enrichment analysis was conducted in the clusterProfiler package. Results Different programmed death pathways were abnormally activated in sepsis patients as compared to normal samples. We screened five important NETosis associated genes, namely, CEACAM8, PGLYRP1, MAPK14, S100A12, and LCN2. These genes were significantly positively correlated with entotic cell death and ferroptosis and negatively correlated with autophagy. A clinical prognostic model based on riskscore was established using the five genes. The ROC curves of the model at 7 days, 14 days and 21 days all had high AUC values, indicating a strong stability of the model. Patients with high riskscore had lower survival rate than those with low riskscore. After the development of a nomogram, calibration curve and decision curve evaluation also showed a strong prediction performance and reliability of the model. As for clinicopathological features, older patients and female patients had a relatively high riskscore. The riskscore was significantly positively correlated with cell cycle-related pathways and significantly negatively correlated with inflammatory pathways. Conclusion We screened five NETosis-associated genes that affected sepsis prognosis, and then established a riskscore model that can accurately evaluate the prognosis and survival for sepsis patients. Our research may be helpful for the diagnosis and clinical treatment of sepsis.
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Affiliation(s)
- Jiahao Wu
- Department of Rehabilitation, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 225002, China
| | - Xingxing Cao
- Department of Rehabilitation, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 225002, China
| | - Linghui Huang
- Department of Rehabilitation, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 225002, China
| | - Yifeng Quan
- Department of Rehabilitation, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, 225002, China
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12
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Chen H, Liu S, Fang G. Knockdown of OLFM4 protects cardiomyocytes from sepsis by inhibiting apoptosis and inflammatory responses. Allergol Immunopathol (Madr) 2024; 52:15-20. [PMID: 39278846 DOI: 10.15586/aei.v52i5.1145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 08/04/2024] [Indexed: 09/18/2024]
Abstract
Sepsis is a systemic inflammatory response that can result in cardiac insufficiency or heart failure known as septic myocardial injury. A previous study identified OLFM4 as an important gene in sepsis through bioinformatics analysis. However, there is limited research on the regulatory functions of OLFM4 in sepsis-triggered myocardial injury, and the related molecular mechanisms remain unclear. In this study, the protein expression of OLFM4 was found to be significantly elevated in LPS-stimulated H9C2 cells, and its suppression enhanced cell proliferation and reduced cell apoptosis in LPS-triggered H9C2 cells. The inflammatory factors TNF-α, IL-6, and IL-1β were increased after LPS treatment, and these effects were mitigated after silencing OLFM4. Moreover, it was confirmed that inhibition of OLFM4 attenuated the NF-κB signaling pathway. In conclusion, the knockdown of OLFM4 protected cardiomyocytes from sepsis by inhibiting apoptosis and inflammatory responses via the NF-κB pathway. These findings provide important insights into the regulatory functions of OLFM4 in the progression of septic myocardial injury.
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Affiliation(s)
- Hailu Chen
- Department of Infectious Diseases and Tropical Diseases, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuna Liu
- Department of Infectious Diseases and Tropical Diseases, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Guihua Fang
- Department of Infectious Diseases and Tropical Diseases, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, China;
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13
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Zhang Z, Tan XJ, Shi HQ, Zhang H, Li JB, Liao XL. Bibliometric study of sepsis-associated liver injury from 2000 to 2023. World J Gastroenterol 2024; 30:3609-3624. [PMID: 39193568 PMCID: PMC11346150 DOI: 10.3748/wjg.v30.i30.3609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/28/2024] [Accepted: 07/16/2024] [Indexed: 08/08/2024] Open
Abstract
BACKGROUND Sepsis-associated liver injury (SLI) is a severe and prevalent complication of sepsis. AIM To explore the literature on SLI via a bibliometric approach. METHODS Reviews and articles correlated with SLI published from January 1, 2000 to October 28, 2023 were searched from the Web of Science Core Collection. Then, the searched data were analyzed using VOSviewer, CiteSpace, and R language. RESULTS There were 787 publications involved in this paper, comprising 745 articles and 42 reviews. China, the United States, and Germany are the primary publication sources in this area. Studies related to SLI primarily focused on mechanisms of pathogenesis, as evidenced by analyzing keywords, references, and the counting of original research. These studies mainly involved tumor necrosis factor alpha, inflammation, oxidative stress, and nuclear factor-kappa B. CONCLUSION There is significant growth in the research on SLI. Current investigations primarily involve basic experiments that aimed at uncovering pathogenic mechanisms. According to the analyzed literature, the identified pathogenic mechanisms and potential therapeutic targets serve as the foundation for translating findings from basic research to clinical applications.
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Affiliation(s)
- Zheng Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Jiao Tan
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hai-Qing Shi
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian-Bo Li
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xue-Lian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Critical Care Medicine, West China Tianfu Hospital of Sichuan University, Chengdu 610200, Sichuan Province, China
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14
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Zhang Z, Tan XJ, Shi HQ, Zhang H, Li JB, Liao XL. Bibliometric study of sepsis-associated liver injury from 2000 to 2023. World J Gastroenterol 2024; 30:3610-3625. [DOI: 10.3748/wjg.v30.i30.3610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/28/2024] [Accepted: 07/16/2024] [Indexed: 08/08/2024] Open
Abstract
BACKGROUND Sepsis-associated liver injury (SLI) is a severe and prevalent complication of sepsis.
AIM To explore the literature on SLI via a bibliometric approach.
METHODS Reviews and articles correlated with SLI published from January 1, 2000 to October 28, 2023 were searched from the Web of Science Core Collection. Then, the searched data were analyzed using VOSviewer, CiteSpace, and R language.
RESULTS There were 787 publications involved in this paper, comprising 745 articles and 42 reviews. China, the United States, and Germany are the primary publication sources in this area. Studies related to SLI primarily focused on mechanisms of pathogenesis, as evidenced by analyzing keywords, references, and the counting of original research. These studies mainly involved tumor necrosis factor alpha, inflammation, oxidative stress, and nuclear factor-kappa B.
CONCLUSION There is significant growth in the research on SLI. Current investigations primarily involve basic experiments that aimed at uncovering pathogenic mechanisms. According to the analyzed literature, the identified pathogenic mechanisms and potential therapeutic targets serve as the foundation for translating findings from basic research to clinical applications.
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Affiliation(s)
- Zheng Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xiao-Jiao Tan
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hai-Qing Shi
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Huan Zhang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian-Bo Li
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xue-Lian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Critical Care Medicine, West China Tianfu Hospital of Sichuan University, Chengdu 610200, Sichuan Province, China
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15
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Fan K, Wang J, Zhu W, Zhang X, Deng F, Zhang Y, Zou S, Kong L, Shi H, Li Z, Shen G, Wang D, Wu Z, Li H, Xu Z. Urinary proteomics for noninvasive monitoring of biomarkers of chronic mountain sickness in a young adult population using data-independent acquisition (DIA)-based mass spectrometry. J Proteomics 2024; 302:105195. [PMID: 38734407 DOI: 10.1016/j.jprot.2024.105195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/28/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024]
Abstract
Different populations exhibit varying pathophysiological responses to plateau environments. Therefore, it is crucial to identify molecular markers in body fluids with high specificity and sensitivity to aid in determination. Proteomics offers a fresh perspective for investigating protein changes linked to diseases. We utilize urine as a specific biomarker for early chronic mountain sickness (CMS) detection, as it is a simple-to-collect biological fluid. We collected urine samples from three groups: plains health, plateau health and CMS. Using DIA's proteomic approach, we found differentially expressed proteins between these groups, which will be used as a basis for future studies to identify protein markers. Compared with the healthy plain population, 660 altering proteins were identified in plateau health, which performed the resistance to altitude response function by boosting substance metabolism and reducing immune stress function. Compared to the healthy plateau population, the CMS group had 140 different proteins identified, out of which 8 were potential biomarkers for CMS. Our study has suggested that CMS may be closely related to increased thyroid hormone levels, oxidative damage to the mitochondria, impaired cell detoxification function and inhibited hydrolase activity. SIGNIFICANCE: Our team has compiled a comprehensive dataset of urine proteomics for AMS disease. We successfully identified differentially expressed proteins between healthy and AMS groups using the DIA proteomic approach. We discovered that 660 proteins were altered in plateau health compared to the healthy plain population, resulting in a heightened resistance to altitude response function by boosting substance metabolism and reducing immune stress function. Additionally, we pinpointed 140 different proteins in the AMS group compared to the healthy plateau population, with 8 showing potential as biomarkers for AMS. Our findings suggest that the onset of AMS may be closely linked to increased thyroid hormone levels, oxidative damage to the mitochondria, impaired cell detoxification function and inhibited hydrolase activity.
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Affiliation(s)
- Kaiyuan Fan
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Jin Wang
- Department of Clinical Laboratory, Tianjin Third Central Hospital, Tianjin 300170, PR China
| | - Wenqing Zhu
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Xinan Zhang
- Xizang Corps Hospital of Chinese People's Armed Police Force, Lasa 850000, PR China
| | - Feng Deng
- Xizang Corps Hospital of Chinese People's Armed Police Force, Lasa 850000, PR China
| | - Yan Zhang
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Shuang Zou
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Lingjia Kong
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - He Shi
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Ziling Li
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Guozheng Shen
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Dong Wang
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China
| | - Zhidong Wu
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China.
| | - Heng Li
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China.
| | - Zhongwei Xu
- Central Laboratory, Logistics University of Chinese People's Armed Police Force, Tianjin 300309, PR China; Tianjin key laboratory for prevention and control of occupational and environmental hazards, Tianjin 300309, PR China.
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16
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Gao M, Dong H, Jiang S, Chen F, Fu Y, Luo Y. Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth. Oncogenesis 2024; 13:21. [PMID: 38871685 DOI: 10.1038/s41389-024-00522-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 05/28/2024] [Accepted: 06/03/2024] [Indexed: 06/15/2024] Open
Abstract
The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.
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Affiliation(s)
- Meng Gao
- Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, China
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Hang Dong
- Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Siyi Jiang
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Fangping Chen
- Department of Hematology, The Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yunfeng Fu
- Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, China.
| | - Yanwei Luo
- Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, China.
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17
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Sage SE, Leeb T, Jagannathan V, Gerber V. Single-cell profiling of bronchoalveolar cells reveals a Th17 signature in neutrophilic severe equine asthma. Immunology 2024; 171:549-565. [PMID: 38153159 DOI: 10.1111/imm.13745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 12/10/2023] [Indexed: 12/29/2023] Open
Abstract
Severe equine asthma (SEA) is a complex respiratory condition characterized by chronic airway inflammation. It shares many clinical and pathological features with human neutrophilic asthma, making it a valuable model for studying this condition. However, the immune mechanisms driving SEA have remained elusive. Although SEA has been primarily associated with a Th2 response, there have also been reports of Th1, Th17, or mixed-mediated responses. To uncover the elusive immune mechanisms driving SEA, we performed single-cell mRNA sequencing (scRNA-seq) on cryopreserved bronchoalveolar cells from 11 Warmblood horses, 5 controls and 6 with SEA. We identified six major cell types, including B cells, T cells, monocytes-macrophages, dendritic cells, neutrophils, and mast cells. All cell types exhibited significant heterogeneity, with previously identified and novel cell subtypes. Notably, we observed monocyte-lymphocyte complexes and detected a robust Th17 signature in SEA, with CXCL13 upregulation in intermediate monocytes. Asthmatic horses exhibited expansion of the B-cell population, Th17 polarization of the T-cell populations, and dysregulation of genes associated with T-cell function. Neutrophils demonstrated enhanced migratory capacity and heightened aptitude for neutrophil extracellular trap formation. These findings provide compelling evidence for a predominant Th17 immune response in neutrophilic SEA, driven by dysregulation of monocyte and T-cell genes. The dysregulated genes identified through scRNA-seq have potential as biomarkers and therapeutic targets for SEA and provide insights into human neutrophilic asthma.
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Affiliation(s)
- Sophie E Sage
- Department of Clinical Veterinary Medicine, Vetsuisse Faculty, Swiss Institute of Equine Medicine, University of Bern, Bern, Switzerland
| | - Tosso Leeb
- Institute of Genetics, Vetsuisse Faculty, Institute of Genetics, University of Bern, Bern, Switzerland
| | - Vidhya Jagannathan
- Institute of Genetics, Vetsuisse Faculty, Institute of Genetics, University of Bern, Bern, Switzerland
| | - Vinzenz Gerber
- Department of Clinical Veterinary Medicine, Vetsuisse Faculty, Swiss Institute of Equine Medicine, University of Bern, Bern, Switzerland
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18
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Zhao M, Wang M, Chen X, Gao Y, Chen Q, Wang L, Bao Q, Sun D, Du W, Xu Y, Xie L, Jiang X, Zhang L, Peng L, Zhang B, Yao Y. Targeting progranulin alleviated silica particles-induced pulmonary inflammation and fibrosis via decreasing Il-6 and Tgf-β1/Smad. JOURNAL OF HAZARDOUS MATERIALS 2024; 465:133199. [PMID: 38103296 DOI: 10.1016/j.jhazmat.2023.133199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 10/12/2023] [Accepted: 12/05/2023] [Indexed: 12/19/2023]
Abstract
Long term exposure to silica particles leads to various diseases, among which silicosis is of great concern. Silicosis is an interstitial lung disease caused by inhalation of silica particles in production environments. However, the mechanisms underlying silicosis remains unclear. Our previous studies revealed that progranulin (Pgrn) promoted the expression of pro-inflammatory factors in alveolar macrophages treated with silica particles and the secretion of extracellular matrix of pulmonary fibroblasts. Nevertheless, the role of Pgrn in silica particles-induced silicosis in vivo was unknown. This study found that silica particles increased Pgrn expression in silicosis patients. Pgrn deficiency reduced lung inflammation and fibrosis in silica particles-induced silicosis mouse models. Subsequently, based on transcriptional sequencing and interleukin (Il) -6 knockout mouse models, results demonstrated that Pgrn deficiency might decrease silicosis inflammation by reducing the production of Il-6, thereby modulating pulmonary fibrosis in the early stage of silicosis mouse models. Furthermore, another mechanism through which Pgrn deficiency reduced fibrosis in silicosis mouse models was the regulation of the transforming growth factor (Tgf) -β1/Smad signaling pathway. Conclusively, Pgrn contributed to silicosis inflammation and fibrosis induced by silica particles, indicating that Pgrn could be a promising therapeutic target.
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Affiliation(s)
- Manyu Zhao
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Mengzhu Wang
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Xuxi Chen
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Ying Gao
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Qing Chen
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Liqun Wang
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Qixue Bao
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Donglei Sun
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Wen Du
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Yunyi Xu
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Linshen Xie
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Xia Jiang
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Ling Zhang
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Lijun Peng
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China
| | - Ben Zhang
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; Departments of Cardiology, Neurology, and Oncology, Hainan General Hospital and Hainan Affiliated Hospital, Hainan Medical University, Haikou 570311, China.
| | - Yuqin Yao
- Molecular Toxicology Laboratory of Sichuan Provincial Education office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China; West China Occupational Pneumoconiosis Cohort Study (WCOPCS) working group, Research Center For Prevention and Therapy of Occupational Disease, West China-PUMC C.C. Chen Institute of Health, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
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Rao Y, Lin H, Rao H, Rao Y, Tang X, Zuo H, Wang Y. Isoegomaketone alleviates inflammatory response and oxidative stress in sepsis lung injury. Allergol Immunopathol (Madr) 2024; 52:16-22. [PMID: 38459886 DOI: 10.15586/aei.v52i2.1030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 12/04/2023] [Indexed: 03/11/2024]
Abstract
BACKGROUND Sepsis is a life-threatening condition characterized by acute organ dysfunction, which frequently leads to acute lung injury (ALI) in approximately 40% of cases. Isoegomaketone (IK) is a constituent of essential oil found in P. frutescens, known for its diverse biological properties, including anti-inflammatory and antitumor effects. However, the regulatory impact of IK on ALI in the context of sepsis remains poorly understood. METHODS Pathological alterations in lung tissues were assessed using hematoxylin and eosin staining. Enumeration of total leukocytes and neutrophils in bronchoalveolar lavage fluid (BALF) was performed using a hematocytometer, while the levels of interleukin (IL)-6, IL-1β, IL-10, and IL-17 in BALF were quantified using enzyme-linked immunosorbent serological assay. In addition, the levels of malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione (GSH) in lung tissues were assessed using respective commercial kits; cell apoptosis was evaluated using the terminal deoxynucleotide transferase--mediated dUTP nick end-labeling assay, and protein expressions were determined through Western blot analysis. RESULTS Our findings revealed that cecal ligation and puncture (CLP) treatment in mice induced severe lung injury, characterized by increased lung injury scores, significant bleeding, neutrophil infiltration, and alveolar edema. However, treatment with IK at a dose of 10 mg/kg ameliorated CLP-induced lung injury, while IK dose of 5 mg/kg showed no significant effect. Additionally, IK treatment at 10 mg/kg reduced CLP-induced inflammation by decreasing levels of IL-6, IL-1β, IL-10, and IL-17. Furthermore, IK at 10 mg/kg attenuated CLP-induced oxidative stress by modulating levels of MDA, MPO, SOD, and GSH. Moreover, IK treatment with a dose of 10 mg/kg activated the nuclear factor erythroid 2-related factor 2-heme oxygenase-1 (Nrf2-HO-1) pathway by enhancing the protein expressions of Nrf2 and HO-1. CONCLUSION This study demonstrates that IK could mitigate the inflammatory response and oxidative stress associated with sepsis-induced ALI, supporting IK as a promising therapeutic agent for the treatment of sepsis-associated ALI.
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Affiliation(s)
- Yunwei Rao
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Hai Lin
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China;
| | - Huan Rao
- Division 1 of Internal Medicine, Zhangshu People's Hospital, Yichun, Jiangxi, China
| | - Yunkun Rao
- Department of General Surgery, Zhangshu Hospital of TCM, Yichun, Jiangxi, China
| | - Xiaoyuan Tang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Huimin Zuo
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
| | - Ying Wang
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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Cai M, Ye H, Zhu X, Li X, Cai L, Jin J, Chen Q, Shi Y, Yang L, Wang L, Huang X. Fibroblast Growth Factor 21 Relieves Lipopolysaccharide-Induced Acute Lung Injury by Suppressing JAK2/STAT3 Signaling Pathway. Inflammation 2024; 47:209-226. [PMID: 37864659 PMCID: PMC10799097 DOI: 10.1007/s10753-023-01905-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 09/04/2023] [Accepted: 09/11/2023] [Indexed: 10/23/2023]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening disease without an effective drug at present. Fibroblast growth factor 21 (FGF21) was reported to be protective against inflammation in metabolic disease in recent studies. However, the role of FGF21 in ALI has been rarely investigated. In this study, it was found that the expression of FGF21 was markedly increased in lung tissue under lipopolysaccharide (LPS) stimulation in vivo, whereas it was decreased in lung epithelial cells under LPS stimulation in vitro. Therefore, our research aimed to elucidate the potential role of FGF21 in LPS-induced ALI and to detect possible underlying mechanisms. The results revealed that the deficiency of FGF21 aggravated pathological damage, inflammatory infiltration, and pulmonary function in LPS-induced ALI, while exogenous administration of FGF21 improved these manifestations. Moreover, through RNA sequencing and enrichment analysis, it was unveiled that FGF21 might play a protective role in LPS-induced ALI via JAK2/STAT3 signaling pathway. The therapeutic effect of FGF21 was weakened after additional usage of JAK2 activator in vivo. Further investigation revealed that FGF21 significantly inhibited STAT3 phosphorylation and impaired the nuclear translocation of STAT3 in vitro. In addition, the aggravation of inflammation caused by silencing FGF21 can be alleviated by JAK2 inhibitor in vitro. Collectively, these findings unveil a potent protective effect of FGF21 against LPS-induced ALI by inhibiting the JAK2/STAT3 pathway, implying that FGF21 might be a novel and effective therapy for ALI.
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Affiliation(s)
- Mengsi Cai
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Huihui Ye
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Xiayan Zhu
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Xiuchun Li
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Luqiong Cai
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Jiajia Jin
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Qiwen Chen
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Yuzhe Shi
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Lehe Yang
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China
| | - Liangxing Wang
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China.
| | - Xiaoying Huang
- Division of Pulmonary Medicine, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou Key Laboratory Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou Medical University, Xuefu North Street, Wenzhou, Zhejiang, 325000, People's Republic of China.
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21
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Qian G, Fang H, Chen A, Sun Z, Huang M, Luo M, Cheng E, Zhang S, Wang X, Fang H. A hub gene signature as a therapeutic target and biomarker for sepsis and geriatric sepsis-induced ARDS concomitant with COVID-19 infection. Front Immunol 2023; 14:1257834. [PMID: 37822934 PMCID: PMC10562607 DOI: 10.3389/fimmu.2023.1257834] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/08/2023] [Indexed: 10/13/2023] Open
Abstract
Background COVID-19 and sepsis represent formidable public health challenges, characterized by incompletely elucidated molecular mechanisms. Elucidating the interplay between COVID-19 and sepsis, particularly in geriatric patients suffering from sepsis-induced acute respiratory distress syndrome (ARDS), is of paramount importance for identifying potential therapeutic interventions to mitigate hospitalization and mortality risks. Methods We employed bioinformatics and systems biology approaches to identify hub genes, shared pathways, molecular biomarkers, and candidate therapeutics for managing sepsis and sepsis-induced ARDS in the context of COVID-19 infection, as well as co-existing or sequentially occurring infections. We corroborated these hub genes utilizing murine sepsis-ARDS models and blood samples derived from geriatric patients afflicted by sepsis-induced ARDS. Results Our investigation revealed 189 differentially expressed genes (DEGs) shared among COVID-19 and sepsis datasets. We constructed a protein-protein interaction network, unearthing pivotal hub genes and modules. Notably, nine hub genes displayed significant alterations and correlations with critical inflammatory mediators of pulmonary injury in murine septic lungs. Simultaneously, 12 displayed significant changes and correlations with a neutrophil-recruiting chemokine in geriatric patients with sepsis-induced ARDS. Of these, six hub genes (CD247, CD2, CD40LG, KLRB1, LCN2, RETN) showed significant alterations across COVID-19, sepsis, and geriatric sepsis-induced ARDS. Our single-cell RNA sequencing analysis of hub genes across diverse immune cell types furnished insights into disease pathogenesis. Functional analysis underscored the interconnection between sepsis/sepsis-ARDS and COVID-19, enabling us to pinpoint potential therapeutic targets, transcription factor-gene interactions, DEG-microRNA co-regulatory networks, and prospective drug and chemical compound interactions involving hub genes. Conclusion Our investigation offers potential therapeutic targets/biomarkers, sheds light on the immune response in geriatric patients with sepsis-induced ARDS, emphasizes the association between sepsis/sepsis-ARDS and COVID-19, and proposes prospective alternative pathways for targeted therapeutic interventions.
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Affiliation(s)
- Guojun Qian
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hongwei Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Anning Chen
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Zhun Sun
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Meiying Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Mengyuan Luo
- Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Erdeng Cheng
- Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shengyi Zhang
- Department of Thoracic Surgery, Songjiang Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiaokai Wang
- Department of Interventional and Vascular Surgery, Xuzhou First People's Hospital, Xuzhou, China
| | - Hao Fang
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Minhang Branch, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan Zhangjiang Institute, Shanghai, China
- Department of Anesthesiology, Shanghai Geriatric Medical Center, Shanghai, China
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Chen P, Chen J, Ye J, Yang L. Identification of an Immune-Related Gene Diagnostic Model and Potential Drugs in Sepsis Using Bioinformatics and Pharmacogenomics Approaches. Infect Drug Resist 2023; 16:5665-5680. [PMID: 37662976 PMCID: PMC10473429 DOI: 10.2147/idr.s418176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Accepted: 08/17/2023] [Indexed: 09/05/2023] Open
Abstract
Purpose Sepsis is an organ dysfunction with high mortality. Early identification, diagnosis, and effective treatment of sepsis are beneficial to the survival of patients. This study aimed to find potential diagnosis and immune-related genes, and drug targets, which could provide novel diagnostic and therapeutic markers for sepsis. Patients and Methods The GSE69063, GSE154918 and GSE28750 datasets were integrated to evaluate immune infiltration and identify differentially expressed genes (DEGs) and immune-related genes. Weighted gene co-expression network analysis (WGCNA) was applied to find the hub module related to immune score and sepsis. Immune-related key genes were screened out by taking interaction of DEGs, immune-related genes, and genes in hub module. Protein-protein interaction (PPI) analysis was used to further screen immune-related hub genes, followed by construction of a diagnostic model based on immune-related hub genes. Functional analysis and drug prediction of immune-related hub genes were, respectively, performed by David software and DGIdb database, followed by expression validation by reverse transcriptase polymerase chain reaction (RT-PCR). Results Totally, 93 immune-related key genes were identified between 561 DEGs, 1793 immune-related genes and 12,459 genes in the hub module of WGCNA. Through PPI analysis, a total of 5 diagnose and immune-related hub genes were further obtained, including IL7R, IL10, CD40LG, CD28 and LCN2. Relationship pairs between these 5 genes and immune cell were identified, including LCN2/IL7R/CD28-activated dendritic cell and IL10-immature B cell. Based on pharmacogenomics, 17 candidate drugs might interact with IL 10, including CYCLOSPORINE. Six candidate drugs might interact with CD28 and 11 with CD40LG, CD40LG and CD28 were drug targets of ALDESLEUKIN. Four significantly enriched signaling pathways were identified, such as T cell receptor signaling pathway, NF-kappa B signaling pathway and JAK-STAT signaling pathway. Conclusion The 5-gene diagnostic model could be used to diagnose and guide clinical immunotherapy for sepsis.
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Affiliation(s)
- Peng Chen
- Department of Urology, General Hospital of Northern Theater Command PLA, Shenyang, People’s Republic of China
| | - Juan Chen
- Department of Oncology, General Hospital of Northern Theater Command PLA, Shenyang, People’s Republic of China
| | - Jinghe Ye
- Department of Urology, General Hospital of Northern Theater Command PLA, Shenyang, People’s Republic of China
| | - Limin Yang
- Department of Urology, General Hospital of Northern Theater Command PLA, Shenyang, People’s Republic of China
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Wu J, Lan Y, Wu J, Zhu K. Sepsis-Induced Acute Lung Injury Is Alleviated by Small Molecules from Dietary Plants via Pyroptosis Modulation. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2023; 71:12153-12166. [PMID: 37537751 DOI: 10.1021/acs.jafc.2c08926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/05/2023]
Abstract
Sepsis-induced acute respiratory distress syndrome (ARDS) has high morbidity and mortality, and it has three major pathogeneses, namely alveolar-capillary barrier destruction, elevated gut permeability, and reduced neutrophil extracellular traps (NETS), all of which are pyroptosis-involved. Due to limitations of current agents like adverse reaction superposition, inevitable drug resistance, and relatively heavier financial burden, naturally extracted small-molecule compounds have a broad market even though chemically modified drugs have straightforward efficacy. Despite increased understanding of the molecular biology and mechanism underlying sepsis-induced ARDS, there are no specific reviews concerning how small molecules from dietary plants alleviate sepsis-induced acute lung injury (ALI) via regulating pyroptotic cell death. Herein, we traced and reviewed the molecular underpinnings of sepsis-induced ALI with a focus on small-molecule compounds from dietary plants, the top three categories of which are respectively flavonoids and flavone, terpenoids, and polyphenol and phenolic acids, and how they rescued septic ALI by restraining pyroptosis.
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Affiliation(s)
- Jiasi Wu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuejia Lan
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611130, China
| | - Jinghan Wu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Keli Zhu
- Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
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Osuru HP, Ikeda K, Atluri N, Thiele RH. Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver. Crit Care 2023; 27:266. [PMID: 37407986 DOI: 10.1186/s13054-023-04551-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/25/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND There is a clear relationship between quantitative measures of fitness (e.g., VO2 max) and outcomes after surgical procedures. Whether or not fitness is a modifiable risk factor and what underlying biological processes drive these changes are not known. The purpose of this study was to evaluate the moderate exercise training effect on sepsis outcomes (survival) as well as the hepatic biological response. We chose to study the liver because it plays a central role in the regulation of immune defense during systemic infection and receives blood flow directly from the origin of infection (gut) in the cecal ligation and puncture (CLP) model. METHODS We randomized 50 male (♂) and female (♀) Sprague-Dawley rats (10 weeks, 340 g) to 3 weeks of treadmill exercise training, performed CLP to induce polymicrobial "sepsis," and monitored survival for five days (Part I). In parallel (Part II), we randomized 60 rats to control/sedentary (G1), exercise (G2), exercise + sham surgery (G3), CLP/sepsis (G4), exercise + CLP [12 h (G5) and 24 h (G6)], euthanized at 12 or 24 h, and explored molecular pathways related to exercise and sepsis survival in hepatic tissue and serum. RESULTS Three weeks of exercise training significantly increased rat survival following CLP (polymicrobial sepsis). CLP increased inflammatory markers (e.g., TNF-a, IL-6), which were attenuated by exercise. Sepsis suppressed the SOD and Nrf2 expression, and exercise before sepsis restored SOD and Nrf2 levels near the baseline. CLP led to increased HIF1a expression and oxidative and nitrosative stress, the latter of which were attenuated by exercise. Haptoglobin expression levels were increased in CLP animals, which was significantly amplified in exercise + CLP (24 h) rats. CONCLUSIONS Moderate exercise training (3 weeks) increased the survival in rats exposed to CLP, which was associated with less inflammation, less oxidative and nitrosative stress, and activation of antioxidant defense pathways.
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Affiliation(s)
- Hari Prasad Osuru
- Department of Anesthesiology, University of Virginia School of Medicine, P.O. Box 800710-0710, Charlottesville, VA, 22908-0710, USA.
| | - Keita Ikeda
- Department of Anesthesiology, University of Virginia School of Medicine, P.O. Box 800710-0710, Charlottesville, VA, 22908-0710, USA
| | - Navya Atluri
- Department of Anesthesiology, University of Virginia School of Medicine, P.O. Box 800710-0710, Charlottesville, VA, 22908-0710, USA
| | - Robert H Thiele
- Department of Anesthesiology, University of Virginia School of Medicine, P.O. Box 800710-0710, Charlottesville, VA, 22908-0710, USA.
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Wang J, Yang H, Zheng D, Sun Y, An L, Li G, Zhao Z. Integrating network pharmacology and pharmacological evaluation to reveal the therapeutic effects and potential mechanism of S-allylmercapto-N-acetylcysteine on acute respiratory distress syndrome. Int Immunopharmacol 2023; 121:110516. [PMID: 37369159 DOI: 10.1016/j.intimp.2023.110516] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023]
Abstract
In this research, we sought to examine the effectiveness of S-allylmercapto-N-acetylcysteine (ASSNAC) on LPS-provoked acute respiratory distress syndrome (ARDS) and its potential mechanism based on network pharmacology. To incorporate the effective targets of ASSNAC against ARDS, we firstly searched DisGeNET, TTD, GeneCards and OMIM databases. Then we used String database and Cytoscape program to create the protein-protein interaction network. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis both identified the potential pathways connected to genes. Cytoscape software was used to build the network of drug-targets-pathways and the SwissDock platform was applied to dock the molecule of ASSNAC with the key disease targets. Correspondingly, an ARDS model was established by instillation of LPS in mice to confirm the underlying action mechanism of ASSNAC on ARDS as indicated by the network pharmacology analysis. Results exhibited that 27 overlapping targets, including TLR4, ICAM1, HIF1A, MAPK1, NFKB1, and others, were filtered out. The in vivo experiments showed that ASSNAC alleviated LPS-induced lung injury by downregulating levels of pro-inflammatory mediators and lung dry-wet ratio. Also, ASSNAC attenuated oxidative stress evoked by LPS via diminishing MDA production and SOD consumption as well as upregulating HO-1 level through Nrf2 activation. Results from western blot, quantitative real-time PCR and immunohistochemistry suggested that ASSNAC developed its therapeutic effects by regulating TLR4/MyD88/NF-κB signaling pathway. In conclusion, our research presented the efficacy of ASSNAC against ARDS. Furthermore, the mechanism of ASSNAC on ARDS was clarified by combining network pharmacology prediction with experimental confirmation.
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Affiliation(s)
- Jinglong Wang
- College of Food Sciences and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang 277160, PR China; Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Huatian Yang
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Dandan Zheng
- College of Food Sciences and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang 277160, PR China; Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Yueyue Sun
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Lulu An
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Genju Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China
| | - Zhongxi Zhao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology of Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China; Key University Laboratory of Pharmaceutics & Drug Delivery Systems of Shandong Province, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China; Pediatric Pharmaceutical Engineering Laboratory of Shandong Province, Shandong Dyne Marine Biopharmaceutical Company Limited, Rongcheng, Shandong 264300, PR China; Chemical Immunopharmaceutical Engineering Laboratory of Shandong Province, Shandong Xili Pharmaceutical Company Limited, Heze, Shandong 274300, PR China.
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Liang G, Wang W, He Z. Sepsis associated with acute lung injury over the period 2012-2021: a bibliometric analysis. Front Physiol 2023; 14:1079736. [PMID: 37398906 PMCID: PMC10307965 DOI: 10.3389/fphys.2023.1079736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 06/07/2023] [Indexed: 07/04/2023] Open
Abstract
Background: Sepsis associated with acute lung injury (ALI) is a common acute and severe disease with severe socioeconomic burden. The aim of this study is to explore the literatures of sepsis associated with ALI from a bibliometric perspective. Methods: Articles and reviews related to sepsis associated with ALI published from 2012 to 2021 in the Web of Science Core Collection were retrieved. Countries, affiliations, journals, authors, references, co-citation and keyword analysis in this field were visually analyzed using WOS citation reports, bibliometric.com, CtieSpace and VOSviewer software. Results: Over the last decade (2012-2021), marked progress has been made in the area of sepsis associated with ALI research. 836 papers were enrolled in this study. China accounts for the most contributors. Articles from the United States has the highest average cited. Shanghai Jiao Tong University, University of California System and Huazhong University of Science Technology were the main contributing institutions. Articles in International Immunopharmacology, Inflammation, Shock and Critical Care were cited the most. Matthay MA and Ware LB were the main contributors to this field. Inflammation and NF-κB have always been the focus of sepsis associated with ALI related research, and programmed cell death (including apoptosis, necroptosis and pyroptosis) may be the important direction of future research. Conclusion: Research on the sepsis associated with ALI is flourishing. The research on programmed cell death is a hot spot and may be a promising research field in the coming years.
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Xu K, Zheng P, Zhao S, Wang J, Feng J, Ren Y, Zhong Q, Zhang H, Chen X, Chen J, Xie P. LRFN5 and OLFM4 as novel potential biomarkers for major depressive disorder: a pilot study. Transl Psychiatry 2023; 13:188. [PMID: 37280213 DOI: 10.1038/s41398-023-02490-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/20/2023] [Accepted: 05/26/2023] [Indexed: 06/08/2023] Open
Abstract
Evidences have shown that both LRFN5 and OLFM4 can regulate neural development and synaptic function. Recent genome-wide association studies on major depressive disorder (MDD) have implicated LRFN5 and OLFM4, but their expressions and roles in MDD are still completely unclear. Here, we examined serum concentrations of LRFN5 and OLFM4 in 99 drug-naive MDD patients, 90 drug-treatment MDD patients, and 81 healthy controls (HCs) using ELISA methods. The results showed that both LRFN5 and OLFM4 levels were considerably higher in MDD patients compared to HCs, and were significantly lower in drug-treatment MDD patients than in drug-naive MDD patients. However, there were no significant differences between MDD patients who received a single antidepressant and a combination of antidepressants. Pearson correlation analysis showed that they were associated with the clinical data, including Hamilton Depression Scale score, age, duration of illness, fasting blood glucose, serum lipids, and hepatic, renal, or thyroid function. Moreover, these two molecules both yielded fairly excellent diagnostic performance in diagnosing MDD. In addition, a combination of LRFN5 and OLFM4 demonstrated a better diagnostic effectiveness, with an area under curve of 0.974 in the training set and 0.975 in the testing set. Taken together, our data suggest that LRFN5 and OLFM4 may be implicated in the pathophysiology of MDD and the combination of LRFN5 and OLFM4 may offer a diagnostic biomarker panel for MDD.
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Affiliation(s)
- Ke Xu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Peng Zheng
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shuang Zhao
- Department of Pathophysiology, Chongqing Medical University, Chongqing, China
| | - Jiubing Wang
- Department of Clinical Laboratory, Chongqing Mental Health Centre, Chongqing, China
| | - Jinzhou Feng
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Ren
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qi Zhong
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Hanping Zhang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiangyu Chen
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianjun Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
| | - Peng Xie
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
- National Health Commission Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Liao W, Xiao H, He J, Huang L, Liao Y, Qin J, Yang Q, Qu L, Ma F, Li S. Identification and verification of feature biomarkers associated with immune cells in neonatal sepsis. Eur J Med Res 2023; 28:105. [PMID: 36855207 PMCID: PMC9972688 DOI: 10.1186/s40001-023-01061-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 02/12/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Neonatal sepsis (NS), a life-threatening condition, is characterized by organ dysfunction and is the most common cause of neonatal death. However, the pathogenesis of NS is unclear and the clinical inflammatory markers currently used are not ideal for diagnosis of NS. Thus, exploring the link between immune responses in NS pathogenesis, elucidating the molecular mechanisms involved, and identifying potential therapeutic targets is of great significance in clinical practice. Herein, our study aimed to explore immune-related genes in NS and identify potential diagnostic biomarkers. Datasets for patients with NS and healthy controls were downloaded from the GEO database; GSE69686 and GSE25504 were used as the analysis and validation datasets, respectively. Differentially expressed genes (DEGs) were identified and Gene Set Enrichment Analysis (GSEA) was performed to determine their biological functions. Composition of immune cells was determined and immune-related genes (IRGs) between the two clusters were identified and their metabolic pathways were determined. Key genes with correlation coefficient > 0.5 and p < 0.05 were selected as screening biomarkers. Logistic regression models were constructed based on the selected biomarkers, and the diagnostic models were validated. RESULTS Fifty-two DEGs were identified, and GSEA indicated involvement in acute inflammatory response, bacterial detection, and regulation of macrophage activation. Most infiltrating immune cells, including activated CD8 + T cells, were significantly different in patients with NS compared to the healthy controls. Fifty-four IRGs were identified, and GSEA indicated involvement in immune response and macrophage activation and regulation of T cell activation. Diagnostic models of DEGs containing five genes (PROS1, TDRD9, RETN, LOC728401, and METTL7B) and IRG with one gene (NSUN7) constructed using LASSO algorithm were validated using the GPL6947 and GPL13667 subset datasets, respectively. The IRG model outperformed the DEG model. Additionally, statistical analysis suggested that risk scores may be related to gestational age and birth weight, regardless of sex. CONCLUSIONS We identified six IRGs as potential diagnostic biomarkers for NS and developed diagnostic models for NS. Our findings provide a new perspective for future research on NS pathogenesis.
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Affiliation(s)
- Weiqiang Liao
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Huimin Xiao
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Jinning He
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Lili Huang
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Yanxia Liao
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Jiaohong Qin
- Department of Pediatrics, Dongguan Houjie Hospital, Dongguan, 523945 China
| | - Qiuping Yang
- grid.488525.6Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655 China
| | - Liuhong Qu
- Department of Neonatology, The Maternal and Child Health Care Hospital of Huadu, Guangzhou, 510800, China.
| | - Fei Ma
- Department of Neonatology, Maternal and Child Health Research Institute, Zhuhai Women and Children's Hospital, Zhuhai, 519001, China.
| | - Sitao Li
- Department of Pediatrics, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
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Al Gharaibeh FN, Kempton KM, Alder MN. Olfactomedin-4-Positive Neutrophils in Neonates: Link to Systemic Inflammation and Bronchopulmonary Dysplasia. Neonatology 2022; 120:40-48. [PMID: 36549285 PMCID: PMC10010669 DOI: 10.1159/000527902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 10/21/2022] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Little is known about the interplay between neutrophil heterogeneity in neonates in health and disease states. Olfactomedin-4 (OLFM4) marks a subset of neutrophils that have been described in adults and pediatric patients but not neonates, and this subset is thought to play a role in modulating the host inflammatory response. METHODS This is a prospective cohort of neonates who were born between June 2020 and December 2021 at the University of Cincinnati Medical Center NICU. Olfactomedin-4-positive (OLFM4+) neutrophils were identified in the peripheral blood using flow cytometry. RESULTS OLFM4+ neutrophil percentage was not correlated with gestational age or developmental age. Neonates with sepsis had a higher percentage than those without the condition, 66.9% (IQR 24.3-76.9%) versus 21.5% (IQR 10.6-34.7%), respectively, p = 0.0003. At birth, a high percentage of OLFM4+ neutrophils was associated with severe chorioamnionitis at 49.1% (IQR 28.2-61.5%) compared to those without it at 13.7% (IQR 7.7-26.3%), p < 0.0001. Among neonates without sepsis, the percentages of OLFM4+ neutrophils were lower in the BPD/early death group compared to those without BPD, 11.8% (IQR 6.3-29.0%) versus 32.5% (IQR 18.5-46.1%), p = 0.003, and this retained significance in a multiple logistic regression model that included gestational age, birthweight, and race. CONCLUSION This is the first study describing OLFM4+ neutrophils in neonates and it shows that this neutrophil subpopulation is not influenced by gestational age but is elevated in inflammatory conditions such as sepsis and severe chorioamnionitis, and lower percentage at birth is associated with developing bronchopulmonary dysplasia.
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Affiliation(s)
- Faris N Al Gharaibeh
- Division of Neonatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Kristalynn M Kempton
- Division of Critical Care, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Matthew N Alder
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Division of Critical Care, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Huang D, Li X, Liu Y, Yang J, Liu J, Zhang M, Liu X, Meng Q, Zhang S, Li H. Significance of differential expression of OLFM4 in the development of endometrial adenocarcinoma. Medicine (Baltimore) 2022; 101:e31858. [PMID: 36451436 PMCID: PMC9704920 DOI: 10.1097/md.0000000000031858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
The incidence of endometrial adenocarcinoma (EA) has increased worldwide in recent years due to the widespread use of estrogen therapy and the overall increase in life expectancy. However, we know of no sensitive molecular index that can be used to predict the onset of EA, evaluate the therapeutic effects of treatment agents, or provide prognostic benefit in post-treatment follow-up. To explore the correlation between human olfactomedin 4 (OLFM4) and the clinicopathologic parameters of EA, and to determine the precise involvement of OLFM4 as a related factor in the occurrence and development of EA. We enrolled 61 gynecologic patients for a retrospective study at the Tai'an Central Hospital of Shandong Province from January 1, 2016, to June 30, 2022. We determined the expression levels of estrogen receptor α (ERα), progesterone receptor (PR), and OLFM4 proteins in endometrial tissue with the immunohistochemical S-P staining method, and analyzed the correlations among ERα, PR, and OLFM4 protein expression levels and with the pathologic stage, histologic grade, myometrial invasiveness, and lymphatic metastasis of EA. The expression levels of OLFM4 in EA were higher than in normal endometrium (P = .036). The expression level of OLFM4 protein in stage II-III patients was higher than that in stage I patients (P = .034), and the expression levels of ERα and PR proteins in EA were lower than those in normal endometrial tissue (P = .014 and P = .0005). While we observed no correlation in endometrial tissues of disparate pathologic types between OLFM4 and the expression levels of ERα and PR proteins, we noted a positive correlation between the expression levels of ERα and PR protein. The expression level of OLFM4 protein increased with the malignant degree of endometrial lesions and OLFM4 protein expression was related to the FIGO stage of EA. And OLFM4 protein can be used as 1 of the potential diagnostic factors for endometrial lesions, which is worthy of further study.
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Affiliation(s)
- Di Huang
- Shandong First Medical University, Jinan, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, China
| | - Xuefei Li
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Yingzi Liu
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Jie Yang
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Jing Liu
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Mingwei Zhang
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Xiulan Liu
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Qi Meng
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Shuheng Zhang
- Taian City Central Hospital of Qingdao University, Taian, China
| | - Hua Li
- Taian City Central Hospital of Qingdao University, Taian, China
- * Correspondence: Hua Li, Taian City Central Hospital of Qingdao University, Taian 271000, China (e-mail: )
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Haas-Neill S, Dvorkin-Gheva A, Forsythe P. Severe, but not moderate asthmatics share blood transcriptomic changes with post-traumatic stress disorder and depression. PLoS One 2022; 17:e0275864. [PMID: 36206293 PMCID: PMC9543640 DOI: 10.1371/journal.pone.0275864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 09/23/2022] [Indexed: 11/24/2022] Open
Abstract
Asthma, an inflammatory disorder of the airways, is one of the most common chronic illnesses worldwide and is associated with significant morbidity. There is growing recognition of an association between asthma and mood disorders including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Although there are several hypotheses regarding the relationship between asthma and mental health, there is little understanding of underlying mechanisms and causality. In the current study we utilized publicly available datasets of human blood mRNA collected from patients with severe and moderate asthma, MDD, and PTSD. We performed differential expression (DE) analysis and Gene Set Enrichment Analysis (GSEA) on diseased subjects against the healthy subjects from their respective datasets, compared the results between diseases, and validated DE genes and gene sets with 4 more independent datasets. Our analysis revealed that commonalities in blood transcriptomic changes were only found between the severe form of asthma and mood disorders. Gene expression commonly regulated in PTSD and severe asthma, included ORMDL3 a gene known to be associated with asthma risk and STX8, which is involved in TrkA signaling. We also identified several pathways commonly regulated to both MDD and severe asthma. This study reveals gene and pathway regulation that potentially drives the comorbidity between severe asthma, PTSD, and MDD and may serve as foci for future research aimed at gaining a better understanding of both the relationship between asthma and PTSD, and the pathophysiology of the individual disorders.
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Affiliation(s)
- Sandor Haas-Neill
- The Brain Body Institute, St. Joseph’s Hospital, McMaster University, Hamilton, Ontario, Canada
| | - Anna Dvorkin-Gheva
- McMaster Immunology Research Centre, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Paul Forsythe
- Alberta Respiratory Centre, Division of Pulmonary Medicine, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Sage SE, Nicholson P, Peters LM, Leeb T, Jagannathan V, Gerber V. Single-cell gene expression analysis of cryopreserved equine bronchoalveolar cells. Front Immunol 2022; 13:929922. [PMID: 36105804 PMCID: PMC9467276 DOI: 10.3389/fimmu.2022.929922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 08/08/2022] [Indexed: 12/21/2022] Open
Abstract
The transcriptomic profile of a cell population can now be studied at the cellular level using single-cell mRNA sequencing (scRNA-seq). This novel technique provides the unprecedented opportunity to explore the cellular composition of the bronchoalveolar lavage fluid (BALF) of the horse, a species for which cell type markers are poorly described. Here, scRNA-seq technology was applied to cryopreserved equine BALF cells. Analysis of 4,631 cells isolated from three asthmatic horses in remission identified 16 cell clusters belonging to six major cell types: monocytes/macrophages, T cells, B/plasma cells, dendritic cells, neutrophils and mast cells. Higher resolution analysis of the constituents of the major immune cell populations allowed deep annotation of monocytes/macrophages, T cells and B/plasma cells. A significantly higher lymphocyte/macrophage ratio was detected with scRNA-seq compared to conventional cytological differential cell count. For the first time in horses, we detected a transcriptomic signature consistent with monocyte-lymphocyte complexes. Our findings indicate that scRNA-seq technology is applicable to cryopreserved equine BALF cells, allowing the identification of its major (cytologically differentiated) populations as well as previously unexplored T cell and macrophage subpopulations. Single-cell gene expression analysis has the potential to facilitate understanding of the immunological mechanisms at play in respiratory disorders of the horse, such as equine asthma.
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Affiliation(s)
- Sophie E. Sage
- Swiss Institute of Equine Medicine, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland
- *Correspondence: Sophie E. Sage,
| | - Pamela Nicholson
- Next Generation Sequencing Platform, University of Bern, Bern, Switzerland
| | - Laureen M. Peters
- Clinical Diagnostic Laboratory, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Tosso Leeb
- Next Generation Sequencing Platform, University of Bern, Bern, Switzerland
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Vidhya Jagannathan
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, Switzerland
| | - Vinzenz Gerber
- Swiss Institute of Equine Medicine, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern, Switzerland
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Qinbaohong Zhike Oral Liquid Attenuates LPS-Induced Acute Lung Injury in Immature Rats by Inhibiting OLFM4. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7272371. [PMID: 36035204 PMCID: PMC9400428 DOI: 10.1155/2022/7272371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/14/2022] [Indexed: 11/17/2022]
Abstract
Acute respiratory infections (ARIs) are a common public safety threat with high morbidity and mortality in pediatric patients worldwide. Qinbaohong Zhike oral liquid (QBH), a marketed traditional Chinese medicine product, has been widely used to cure respiratory diseases. QBH is reported to have antitussive, expectorant, and antiasthmatic properties. However, its treatment effect against ARIs is not elucidated. This study aimed to explore the therapeutic efficacy of QBH in the treatment of ARIs-induced pneumonia. Network pharmacology was used to predict the possible targets of QBH against ARIs. Next, the tracheal lipopolysaccharide (LPS-)-induced acute lung injury (ALI) immature rat model was constructed to evaluate the therapeutic effect of QBH. Tandem mass tag (TMT-)-based quantitative proteomics was then used to screen the in-depth disease targets of QBH. QBH exerted a protective effect against LPS-induced ALI by inhibiting pulmonary pathological damage. QBH also reduced the levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and granulocyte macrophage colony-stimulating factor (GM-CSF) in the serum and IL-1β, IL-6, IL-8, TNF-α, IFN-γ, and GM-CSF in the lung tissue. Based on proteomic data, olfactomedin 4 (OLFM4) related to immunity and inflammation was selected as a potential target. Western blot analysis further confirmed the moderating effect of QBH downregulation on OLFM4 in the lung tissue. Our findings demonstrated that QBH alleviated lung tissue damage and inflammatory reaction via inhibiting OLFM4 expression in LPS-challenged immature rats. Our research indicates that QBH may have therapeutic potential for treating ARIs-related ALI in pediatric patients, which also serves as a candidate target for drug therapy of ALI by intervening OLFM-related signaling pathways.
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Li C, Zhu H, Zhang S, Meng F, Li S, Li G, Zha J, Wu S, Zhu L, Dai A. Astragaloside IV ameliorates pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension by restraining the T follicular helper cell response and expanding T follicular regulatory cell response. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 102:154171. [PMID: 35636165 DOI: 10.1016/j.phymed.2022.154171] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/11/2022] [Accepted: 05/12/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Pulmonary hypertension (PH) is a progressive disorder lacking a validated and effective therapy which characterized by elevated pulmonary arterial pressure, vascular remodeling and eventual death. FDA approved sildenafil is being used as a first-line drug for PH, however, neither survival rates nor quality of life have been improved because of side effects and patient noncompliance. Thus, the exploration of novel therapeutic drugs is urgently needed. Astragaloside IV (ASIV) exhibits a protective effect on HPH, but its mechanisms of action is unclear. HYPOTHESIS CD4+T cell subsets, Tfh and Tfr cells, may contribute to the development of chronic hypoxia-induced PH (HPH). We hypothesized that ASIV could effectively ameliorates pulmonary vascular remodeling of HPH by restraining the Tfh cell response and expanding Tfr cell response. METHODS AND RESULTS HPH mice model was established by exposure to chronic hypoxia for 21 days. Mice were randomly assigned to six groups: NaCl group, model group, SN group (100 mg/kg of sildenafil), low-dose group (20 mg/kg of ASIV), medium-dose group (40 mg/kg of ASIV) and high-dose group (80 mg/kg of ASIV). Primary culture and identification of distal pulmonary artery smooth muscle cells (PASMCs) in mice were established. Here, we demonstrated that ASIV treatment could significantly ameliorate the increase of mean PAP, RV/ (LV+S) ratio and PAMT in HPH mice. ASIV inhibited Tfh cell differentiation and IL-21 production, but promoted Tfr cell differentiation and TGF-β, IL-10 production. Chronic hypoxia promoted germinal center B cell responses, which inhibited by ASIV. ASIV regulated Tfh and Tfr cell differentiation by inhibiting the phosphorylation of mTOR signaling pathway, and the effect of ASIV-H was better than that observed in the SN group. ASIV inhibited the proliferation, migration and adhesion of PASMCs in vitro. Moreover, ASIV significantly downregulated the protein level of RhoA and upregulated the protein level of p27 in PASMCs under hypoxic condition. CONCLUSION Collectively, ASIV may regulate Tfh and Tfr cell responses to subsequently repress pulmonary vascular remodeling and hypoxic pulmonary hypertension.
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Affiliation(s)
- Cheng Li
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - Hao Zhu
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - Shaoze Zhang
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - Fang Meng
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - San Li
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - Guang Li
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China
| | - Jun Zha
- Department of Respiratory Diseases, Medical School, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China
| | - Shangjie Wu
- Department of Respiratory and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China
| | - Liming Zhu
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China.
| | - Aiguo Dai
- Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of HunanNormal University, Changsha, Hunan 410016, PR China; Department of Respiratory Diseases, Medical School, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China.
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